The objectives of this research project are to provide a better understanding of the mechanism by which insulin resistance develops in various animal models of obesity, hyperinsulinemia and impaired glucose tolerance and to determine the mechanism by which exercise and physical training improve tissue sensitivity and/or responsiveness to insulin. In addition to studies in normal rats, the effects of exercise and physical training on the insulin resistance which develops in obese Zucker (fa/fa) rats, normal Sprague-Dawley rats as they become older and more obese, chronically hyperinsulinemic rats and rats made mildly to moderately diabetic with streptozotocin will be examined. Parallel studies will be done in skeletal muscle, liver and adipose cells, the 3 major target tissues of insulin action. Insulin action in muscle will be characterized by measuring 125I-labeled insulin binding, 2-deoxy-d-glucose transport, and incorporation of D-[3H-5]-glucose into glycogen and 3H2O in soleus and epitrochlearis muscles incubated in vitro. The number of glucose transport units and their distribution between muscle plasma membranes and the intracellular pool will be determined to test the hypotheses that exercise increases glucose transport activity in muscle by producing a translocation of glucose transport units from the intracellular pool into plasma membranes and that physical training results in an increase in total glucose transport unit number. It is proposed that, decreased glucose transport unit number, altered cellular distribution or failure of exercise and/or insulin to produce normal translocation into plasma membranes may play a major role in the development of insulin resistance in muscle, in a manner similar to that which occurs in adipose cells. Studies in incubated muscles and adipose cells will be correlated with measurements of insulin sensitivity and responsiveness in vivo using the hyperinsulinemic-euglycemic clamp technique; with plasma concentrations of glucose, insulin, FFA and triglycerides and with muscle and liver contents of glycogen and triglyceride. In addition, the hyperinsulinemic-euglycemic clamp technique will be used to measure hepatic glucose production and its sensitivity to suppression by insulin in sedentary, exercised and physically trained animals.